Integrated Continuous Manufacturing (ICM), consists of a series of unit operations that operate in flow and are integrated into a seamless end-to-end (from synthesis to final product) manufacturing process. ICM represents a shift from the batch manufacturing processes used in the pharmaceutical industry. In contrast to batch manufacturing, ICM's unit operation integration process results in significant operational advantages. ICM significantly reduces manufacturing costs (>50% reduction) and lead times (>90% reduction), has a smaller footprint (˜90% reduction), and provides higher quality drugs. These advantages were demonstrated in the first-of-its kind ICM pilot plant (capacity of 1.5 tons of Active Pharmaceutical Ingredient (API)/year) at MIT, which was able to produce finished coated tablets from raw ingredients through a single, seamless end-to-end process. See Mascia, et al., “End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation,” Angewandte Chemie International Edition, 52(47):12,359-12,363 (2013).
Current pharmaceutical manufacturing consists of unconnected individual steps in large batch units including chemical reactions, filtering, precipitating, drying, milling, and tableting. Quality is evaluated by testing at each step (e.g., quality by testing, QbT). This batch process is plagued by long lead times, geographical dispersion of unit operations, and large manufacturing footprints. It is estimated that more than $50 billion a year is wasted due to inefficient manufacturing. Meanwhile, attempts to improve quality have resulted in increasing numbers of product recalls.
In contrast to the quality by testing approach of the batch manufacturing process, for ICM processes, quality is designed into the system (Quality by Design, QbD). In QbD processes, controllers maintain quality thresholds throughout the production cycle, ensuring that the end product of the entire process meets its quality specification. To create ICM systems, devices and methods for each of the various unit operations need to be developed that can process streams of materials. Further, the unit devices require the ability to adjust to variations in the process stream and to provide feedback to the ICM process controller. The unit devices may include a variety of real-time sensors and Process Analytical Technologies (PATs) to detect changes in process parameters. The ICM process controller integrates the signals across the unit operations and adjusts the parameters to limit the variation within the product stream. Current unit devices, designed to be used in batch mode are generally incompatible with ICM processes, operate at inappropriate scales, do not provide for real time control.
There is a need for the development of unit operation processes and devices that can be incorporated into ICM methods. The present disclosure relates and is directed to methods and devices for the preparation of dried solids from slurries. The solids can be intermediate products or a final active pharmaceutical ingredient (API). The continuous drying apparatuses of the present disclosure are designed to accept a continuous stream of input slurry and output a continuous stream of dried solid with a defined residual moisture content.
There exists a number of patents directed to drum dryers including U.S. Pat. No. 7,272,894 issued to Ajinomoto Co., Inc. on Sep. 25, 2007, European Patent Publication No. EP0170235 to Henkel Corporation dated Feb. 5, 1986, U.S. Pat. No. 3,478,439 issued to Quaker Oats Co. on Nov. 18, 1969, U.S. Pat. No. 3,363,665 to Beloit Corp. on Jan. 16, 1968, U.S. Pat. No. 3,299,527 to Du Pont on Jan. 24, 1967, and U.S. Pat. No. 2,903,054 to Davenport Machine and Foundry on Sep. 8, 1959, each or which are hereby incorporated by reference in their entireties.
During the development and manufacture of pharmaceuticals, the need to prepare dried solids from slurries and solutions containing an intermediate product or active pharmaceutical ingredient (API) occurs regularly. A variety of approaches have been developed including spray dryers, freeze driers, filtration dryers, single drum dryers, agitated paddle dryers, fluidized bed dryers, and spin flash dryers. Conventional oven dryers often used for drying a slurry suffer from a number of deficiencies that make them unsuitable for use in continuous production methods. First, most conventional oven dryers are significantly larger than the continuous drying apparatus as provided in the present specification. The large footprints typical of conventional dryers largely preclude their use in compact continuous production systems. While some conventional dryers can be operated under a vacuum, including a vacuum in the process generally limits the drying process to a batch mode. Accordingly, conventional drying systems are generally designed to be operated in batch mode (like the production of pharmaceuticals themselves) and they cannot be readily integrated into continuous systems. Existing systems, designed for batch-wise use also do not incorporate features that provide for the flexible control and adjustment of the drying rate, the slurry input rates, removal of dried materials, and the recovery of liquids that are essential to a complete continuous production system. In addition, conventional oven dryers, and other approaches, also require personnel to load and unload the material in the dryer resulting in potential exposure of the personnel to hazardous substances and also increasing the risk of contamination (and loss) of the pharmaceutical product. Finally, in addition to batch processing, conventional systems often require extended residence times (e.g., >12 hours) that can result in product degradation and agglomeration.
Fluidized bed dryers, which can be run continuously or in batch, have also been used but suffer from the disadvantage of operating under positive pressure, and cannot operate in a vacuum. This approach also suffers from several other limitations. First, fluidized bed dryers are generally much larger than the devices described in the present specification and are therefore difficult to integrate into a continuous process system for the production of a pharmaceutical. Similarly, fluidized bed dryers require large throughput to be effective; they are not flexible to process smaller volumes nor can they readily accommodate changes in flow and slurry characteristics. Simply shrinking the size of a fluidized bed dryer results in unacceptable inefficiencies. Another disadvantage of fluidized bed dryers is that they operate at high temperature and present unacceptable risks of thermal degradation to the intermediate, API, or drug product. Finally, like the conventional dryer, fluidized bed dryers can have long residence times (e.g. >4 hours), which can result in product degradation and agglomeration.
There are continuous dryers that are currently used in industry. For example, Artisan Industries has developed a thin/wiped-film evaporator (Protherm® 50); however, there are several limitations. First the system is designed for solvent recovery or producing a liquid product or wet powder, not specifically to dry a solution to obtain a dry powder product. Because the Artisan system uses horizontal, agitated vacuum evaporation, it is limited to 10-25 L/hr, with a limited 0.5 ft2 evaporative surface. Second, the system cannot dry slurries containing entrained solvent. Third the Artisan system is large, cart-mounted, and cannot fit into a fume hood, thereby reducing flexibility in drug development using continuous production methods.
Artisan Industries also produces an agitated dryer (Rototherm® D); however, this technology also has several limitations. First, the system is designed to remove moisture or solvent from powders and slurries, especially for applications requiring long residence times (20 minutes to several hours). Second, the system uses a horizontal, agitated vacuum drying system that has only a 2 ft2 evaporative surface. Finally, the system is skid-mounted, and cannot fit into a fume hood (reduced flexibility in drug development).
A continuous drum dryer was developed at the Novartis-MIT Center for Continuous Manufacturing. This unit operation was very effective, and was able to dry a slurry of approximately 5-15 wt %. solid, though not below 1 wt %. There are significant advantages over current dryers, including reduced residence time of the drum dryer (approximately 1 minute), which is much shorter than conventional dryers (residence times often >12 hours). Reduced residence time also reduces the probability of agglomeration and degradation. The unit operation was automated and did not require intensive labor to operate it. Finally, the unit operation had a significantly smaller footprint than corresponding batch ovens.
However, there were also several limitations to the Novartis-MIT technology. First, the unit used convective drying, which places the system under positive pressure, making collection of the dried powder difficult (the dried powder was dispersed by the positive pressure). A convective drying approach precludes the incorporation of a vacuum system to the drying process. The Novartis-MIT continuous dryer system prevented the use of very low temperatures and short residence times and decreased the overall drug purity levels (possibly due to thermal degradation). Using the Novartis-MIT continuous dryer system, dilute pharmaceutical suspensions (for example API solid wt % 5-15%) could not be easily handled. For example, the Novartis-MIT continuous dryer system included a fixed drum gap so that the changing flow rate, changing slurry viscosity, and other variations in the continuous process were not able to be accommodated in real time through automated control. The inability of the previous continuous dryer system to respond real-time to changing material viscosities (for example, due to step-changes in initial API concentration) is a significant disadvantage and hinders the development of fully automated systems, with control parameters adjustable through appropriate code manipulation. The Novartis-MIT continuous drum dryer systems required significant intervention to maintain a continuous steady-state operation.
Accordingly there existed a need to provide a continuous drum dryer system for incorporation into ICM processes that could be adjusted to accommodate changes in slurry input, changes in concentrations, and other variations inherent in a continuous process. The system further needed to be capable of providing for a vacuum to allow for lower temperature drying and reduced residence times. It was also desirable to develop a continuous dryer having a small footprint so that it could be moved and adapted to different continuous production processes and could be isolated within an appropriate containment system, such as a fume hood. The present disclosure further provides for real time monitoring of process parameters including drying temperature, residual moisture content, vacuum pressure, and video monitoring. Finally, the apparatus of the present disclosure provides for the recovery of the liquid from the slurry, improving safety and environmental sustainability.